CN1127256A - New A-nor steroid-3-carboxylic acid derivatives - Google Patents

Abstract

The present invention relates to novel A-nor-steroid-3-carboxylic acid derivatives and to their use as inhibitors of mammalian 5 alpha -reductase.

Description

New A-nor steroid-3-carboxylic acid derivatives

This is a continuation-in-part of Application No. 458,869 filed December 29, 1989. The present invention relates to novel A-nor steroid-3-carboxylic acid derivatives and their use as mammalian steroid 5-alpha-reductases.

Mammalian 5-α-reductase is an enzyme present in mammalian tissues, including skin, male genitalia and prostate, which catalyzes the conversion of the steroid hormone testosterone to the steroid hormone dihydrotestosterone (5-α- androstane-17-β-ol-3-one) conversion. Testosterone and dihydrotestosterone (DHT) belong to the class of androgens, which are primarily responsible for the physical characteristics that distinguish males from females. Testosterone and DHT are the native androgenic steroids in males. However, DHT, and not testosterone, is the most potent androgen end-organ effector in certain tissues, particularly in regulating growth. Furthermore, DHT is primarily formed in target cells by the reduction of testosterone by 5-alpha-reductase.

The skin is known to be responsive to androgens and is the active site of androgen metabolism. Specifically, testosterone is metabolized to DHT in the skin by the action of 5-alpha-reductase. The metabolism of testosterone in the skin can sometimes be abnormally excessive and have adverse effects. There is considerable evidence that DHT is involved in the pathogenesis of acne, including acne vulgaris, and other androgen-related disorders [see Price, Arch. Dermatol. 111, 1496 (1975)]. Therefore, agents capable of preventing the formation of DHT from testosterone in the skin (for example by inhibiting the activity of 5-alpha-reductase) would be effective in the treatment of acne.

In addition, other medical conditions and disease states, including benign prostatic hypertrophy, androgenic alopecia (common androgen-induced baldness in genetically predisposed men and women), seborrhea, and female hirsutism, are associated with increased androgenic activity related. Agents that prevent the formation of DHT from testosterone are also effective in the treatment of these conditions.

其中The present invention provides a new formula (A), (B), nor steroid-3-carboxylic acid derivatives shown in (C) or (D) or

in

Dashed lines represent dispensable double bonds;

R ₁ is hydrogen, C _1-6 alkyl or -(CH ₂ )x-Ar-(M)y, where x is 0, 1 or 2, Ar is phenyl, y is 0, 1 or 2, and M is C ₁ -C ₆ alkoxy, halogen, C ₁ -C ₆ alkyl, or -S(O)zR ₅ , wherein R ₅ is C ₁ -C ₆ alkyl, Z is 0, 1 or 2;

R ₂ is C ₁ -C ₆ alkanol; C ₁ -C ₆ alkanone; CON(R ₃ )(R ₄ ), wherein R ₃ and R ₄ are each independently hydrogen or C ₁ -C ₆ alkyl , or -(CH ₂ )x-Ar-(M)y, where x is 0, 1 or 2, Ar is phenyl, y is 0, 1 or 2, M is C ₁ -C ₆ alkoxy, halogen , C ₁ -C ₆ alkyl, or -S(O)zR ₅ , wherein R ₆ is C ₁ -C ₆ alkyl, and Z is 0, 1 or 2.

The present invention also provides a method for inhibiting 5-alpha-reductase in a patient in need thereof, comprising administering to said patient a therapeutically effective 5-alpha-reductase inhibitory amount of formula (A), (B), (C), the compound of (D).

The term "R ₁ " is defined as hydrogen, C ₁ -C ₆ alkyl or -(CH ₂ )x-Ar-(M)y. The term "C ₁ -C ₆ alkyl" as used herein refers to a straight chain, branched chain or cyclic saturated alkyl group of 1-6 carbon atoms. Included within the scope of this term are methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, cyclohexyl and the like. "-(CH ₂ )x-" means a linear alkylene group wherein x is 0, 1 or 2. The term "-Ar-(M)y" refers to unsubstituted (y=0), monosubstituted (y=1) or disubstituted (y=2) phenyl or naphthyl groups described by "M" . The term "M" refers to C ₁ -C ₆ alkoxy, halogen, C ₁ -C ₆ alkyl, or -S(O)zR ₅ .

The term "C ₁ -C ₆ alkoxy" as used herein refers to a straight chain, branched chain or cyclic saturated alkyl group with oxy group having 1-6 carbon atoms. Included within the scope of this term are: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, Cyclohexyl, etc. The term "halogen" or "halo" as used herein refers to a fluoro, chloro, bromo or iodo group.

The term "C ₁ -C ₆ alkanol" as used herein refers to a straight-chain, branched-chain or cyclic saturated alkyl group with a hydroxyl group of 1-6 carbon atoms. Groups included within the scope of this term are:

_-CH2OH ; -CH(OH) _CH3 ; -C( _CH3 ) _2OH ;

-CH(OH) _CH2CH3 ; _-CH (OH) _CH2CH ( _CH3 ) ₂ ;

-CH( _CH3 ) _CH2OH ; and

The term "C ₁ -C ₆ alkanone" as used herein refers to a straight-chain, branched-chain or cyclic saturated alkyl group with a double bonded oxygen atom of 1-6 carbon atoms. Included within the scope of this term are: -CH=0; -C(O) _CH3 ; -CH(O) _CH2CH3 ; -CH( _O )CH( _CH3 ) ₂ ;

The term "CON(R ₃ )(R ₄ )" as used herein refers to carboxamide, wherein R ₃ and R ₄ are each independently hydrogen, C ₁ -C ₆ alkyl as defined above or -(CH ₂ )x-Ar-(M)y.

The A-norsteroid-3-carboxylic acid derivatives of the present invention, ie compounds of formulas (A), (B) (C) and (D), can be prepared by conventional methods and techniques well known in the art.

A general synthetic procedure for the preparation of compounds of formula (A) is shown in Scheme A. In Scheme A, all substituents are as previously defined. Furthermore, the term "R ₁ '" refers to all groups defined by R ₁ except hydrogen.

Option A

Plan A continued

In general, suitable compounds of formula (A) can be prepared from suitable steroid derivatives of structure (1) in a five-step process.

In step a, the alkene functionality of a suitable steroid derivative of structure (1) is oxidized to the corresponding epoxide functionality. For example, epoxy steroids of structure (2) can be prepared by oxidation of steroid derivatives of structure (1) with hydrogen peroxide in a suitable solvent system such as a mixture of tetrahydrofuran and methanol in the presence of a base such as sodium hydroxide derivative.

In step (b), the epoxy functionality of the epoxy steroid derivative of structure (2) is converted into the corresponding enol ether functionality. For example, enol ether steroids of structure (3) can be prepared by enol ether addition/epoxy functionality elimination of steroid derivatives of structure (2) with sodium methoxide in a suitable alcoholic solvent such as methanol.

In step (c), the ketone function of the enol ether steroid of structure (3) is reduced to the corresponding alcohol function. For example, the enol ether steroids of structure (3) can be reduced to the corresponding hydroxy steroid derivatives of structure (4) with sodium borohydride in a suitable aprotic solvent such as ethanol.

In step (d), the hydroxy steroid derivative of structure (4) is converted into the corresponding 4-keto- ^Δ5 -steroid derivative of structure (5). For example, hydroxysteroid derivatives of structure (4) can be hydrolyzed to the corresponding 4-keto- ^Δ5- steroid derivatives.

^The _formula A-nor- ^Δ5 -steroid-3-carboxylate of ( _A1 ). This treatment leads to ring shrinkage and esterification of the 4-keto- ^Δ5 -steroid derivative of structure (5) to the corresponding A-nor- ^Δ5 -steroid-3-carboxylate derivative (A ₁ ).

Treatment of the 4-keto- ^Δ5 -steroid derivatives (5) with base leads to the formation of the corresponding cross-conjugated dienol esters. Preferred strong bases for this reaction are alkali metal hydroxides such as potassium hydroxide and sodium hydroxide.

Electrophilic addition of hypervalent iodine or thallium III salts to the enol ester is then carried out at the 3-position of the cross-conjugated enol ester. Hypervalent iodine addition is preferred. Reagents with hypervalent iodine suitable for this reaction are reagents such as iodosobenzene. Iodosobenzene is a preferred reagent for the above reaction. Iodosobenzene can be prepared by methods well known in the art. It can be added directly to the reaction mixture or prepared in situ by adding a precursor such as iodobenzene diacetate to the reaction mixture containing the base.

The alcohol (R ₁ 'OH) present in the reaction mixture reacts chemically with the 3-keto group to give the corresponding A-nor-Δ ⁵ -steroid-3-carboxylate derivative (A ₁ ). To obtain a compound of the invention in which _R1 is a substituent other than hydrogen, the appropriate alcohol ( _R1'OH ) can be chosen to provide the desired substituent _R1 ' in the final product. For example, to obtain a compound of formula (A) wherein _R1 is ethyl, ethanol can be used in step e. Likewise, to obtain compounds of formula (A) wherein R ₁ is benzyl, hydroxymethylbenzene can be used in step e. Alternatively, compounds of formula (A) wherein _R1 is other than hydrogen can be prepared from compounds of formula (A) wherein _R1 is hydrogen by conventional esterification methods well known in the art.

In step f, the ester functionality of the appropriate A-nor- ^Δ5 -steroid-3-carboxylate derivative (A) can be converted to the corresponding carboxylic acid functionality under carefully controlled conditions. For example, the appropriate A-nor- ^Δ5 -steroid-3-carboxylic acid can be converted to The ester derivative (A ₁ ) is converted into the corresponding A-nor-Δ ⁵ -steroid-3-carboxylic acid derivative (A ₂ ).

The starting steroid derivative (1) is chosen to provide the desired _R2 substituent in the final product. Steroid derivatives with suitable _R2 substituents are readily available and can be prepared from available derivatives by methods and techniques well known to those of ordinary skill in the art.

The following examples describe typical syntheses shown in Scheme A. These examples are illustrative only and are not intended to limit the scope of the invention in any way. The following terms used in the following examples have the indicated meanings: "g" means gram, "mmol" means millimole, "ml" means milliliter, "°C" means degree Celsius, "TLC" means thin For layer chromatography, "mg" means milligram, "THF" means tetrahydrofuran, "μl" means microliter, and "HPLC" means high pressure liquid chromatography.

In addition, for the designation of specific compounds listed herein, the term "20α" refers to a compound having an S-absolute configuration at the 20-position.

Example 1

17β-(N,N-diisopropylcarboxamide)-A-nor-androst-5-ene

-3α-carboxylic acid and its methyl ester

Step a: 17β-(N,N-diisopropylcarboxamide)-andro-4-5-

Epoxy-3-one

3-Oxo-4-androstene-17β-carboxylic acid (11.2g, 35.4mmol) and dichloromethane (100ml) were mixed, placed under nitrogen atmosphere and cooled to 0°C with an ice bath. Triethylamine (4.1 g, 40.6 mmol) was added followed by dropwise addition of oxalyl chloride (3.8 ml, 4.4 mmol). Warm to 25°C and stir for 30 minutes. The reaction mixture was cooled to 0 °C and additional oxalyl chloride (2.91 g, 22.9 mmol) was added dropwise. Warm to 25°C and stir for 1 hour. Cool to 0°C and add diisopropylamine (23.7ml, 169mmol) dropwise, keeping the temperature below 40°C. Stir overnight at 25°C, add ice water and separate the organic phase. The aqueous phase was extracted with ethyl acetate (2x) and the combined organic phases were washed with 10% hydrochloric acid, 10% potassium hydroxide, water, then saturated sodium chloride. Drying and evaporation of the solvent in vacuo gave the crude product. Purification by silica gel chromatography afforded 17β-(N,N-diisopropylcarboxamide)-androst-4-en-3-one.

17β-(N,N-Diisopropylcarboxamide)-androst-4-en-3-one (10 g, 25 mmol) was dissolved in tetrahydrofuran (40 ml) and methanol (25 ml). Cool to 5°C and treat with 30% hydrogen peroxide (10.8ml) and 10% sodium hydroxide (5ml). When the reaction was complete, the solvent was evaporated in vacuo without heating, and the residue was taken up in ethyl acetate/water. The organic phase was separated and washed well with water and then with saturated sodium chloride. Drying ( _MgSO4 ) and evaporation of the solvent in vacuo gave 10.5 g of the crude title epoxide.

Step (b): 17β-(N,N-diisopropylcarboxamide)-andro-4-

En-4-methoxy-3-one

Sodium hydroxide (10 g) was dissolved in hot methanol (125 ml) and heated to reflux. A solution of 17β-(N,N-diisopropylcarboxamide)-androst-4,5-epoxy-3-one (10.5 g) in methanol (10 ml) was added with stirring. Stir for 15 minutes, pour into water and extract into ethyl acetate. The organic phase is separated, washed with water and dried. The solvent was evaporated in vacuo and purified by silica gel chromatography (25% ethyl acetate/hexanes) to give 1.5 g of the title compound as a crystalline solid; mp 223-225°C. NMR-ppmδ(CDCl ₃ ) 300MHz: 4.19(h, 1H, J=7Hz); 3.60(s, 3H); 3.40(h, 1H, J=7Hz); 3.08(dt, 1H, Jd=10Hz, Jt= 2Hz); 2.63(t, 1H, J=7Hz); 1.43(d, 3H, J=7Hz); 1.40(d, 3H, J=7Hz); 1.23(d, 3H, J=7Hz); 1.21(2 , 3H); 1.15(d, 3H, 7Hz); 0.82(s, 3H).

Step c: 17β-(N,N-diisopropylcarboxamide)-androst-4-ene-

  4-Methoxy-3-ol

Dissolve 17β-(N,N-diisopropylcarboxamide)-androst-4-ene-4-methoxy-3-one (2.0g, 4.6mmol) in absolute ethanol (20ml) and place under nitrogen atmosphere Down. Treat with sodium borohydride (100 mg) at 25°C for 2 hours. Add water and stir for 30 minutes. The solution was poured into ethyl acetate, the organic phase was separated and washed well with water. Drying ( _MgSO4 ) and evaporation of the solvent in vacuo gave 1.9 g of the title compound as a solid.

Step d: 17β-(N,N-Diisopropylcarboxamide)-androst-5-ene-

4-keto

17β-(N,N-diisopropylcarboxamide)-androst-4-ene-4-methoxy-3-ol was dissolved in freshly distilled acetone (20ml) and anhydrous dichloromethane (15ml). Add 70% perchloric acid (4 drops) and stir at 25°C. After 10 minutes, the yellow solution was poured into saturated sodium bicarbonate and extracted into dichloromethane. The organic phase was separated and dried ( _MgSO4 ). Purification by silica gel chromatography (20% ethyl acetate/hexanes) gave 1.0 g of the title compound; mp 138-139°C.

NMR-ppm δ(CDCl ₃ ) 300 MHz: 6.42 (dd, 1H, J ₁ =5 Hz, J ₂ =3 Hz); 4.23 (h, 1H, J = 7 Hz); 3.39 (h, 1H, J = 7 Hz); 2.64 ( t, 1H, J=7Hz); 1.42(d, 3H, J=7Hz); 1.37(d, 3H, J=7Hz); 1.22(d, 3H, J=7Hz); 1.13(d, 3H, J=7Hz); 7Hz); 0.96(s, 3H); 0.78(s, 3H).

Step e: 17β-(N,N-diisopropylcarboxamide)-A-to

Methyl-androst-5-ene-3α-carboxylate

Potassium hydroxide (110 mg) was dissolved in dry methanol (2 ml), placed under a nitrogen atmosphere and cooled to 0°C. 17β-(N,N-Diisopropylcarboxamide)-androst-5-en-4-one (120 mg, 0.30 mmol) was added, followed by iodobenzene diacetate (200 mg, 0.60 mmol). Stir light yellow solution at 0-5°C

1 hour and poured into dilute hydrochloric acid. Extracted into dichloromethane, separated the organic phase and dried ( _MgSO4 ). The solvent was evaporated in vacuo and the residue was treated with excess diazomethane. The solvent was evaporated in vacuo to give the title compound as a yellow film. NMR-ppmδ(CDCl ₃ ) 300MHz: 5.48(m, 1H); 4.23(h, 1H, J=7Hz); 3.70(s, 3H); 3.41(h, 1H, J=7Hz); 2.65(t, 1H , J=7Hz); 1.43(d, 3H, J=7Hz); 1.40(d, 3H, J=7Hz); 1.22(d, 1H, J=7Hz); 1.15(d, 3H, J=7Hz); 0.95(s, 3H); 0.78(s, 3H).

Step f: 17β-(N,N-diisopropylcarboxamide)-A-to

A-androst-5-ene-3α-carboxylic acid

Dissolve 17β-(N,N-diisopropylcarboxamide)-A-nor-androst-5-ene-3α-carboxylate methyl ester (100mg, 0.233mmol) in dichloromethane (3ml) and wash with trimethyl Treat with silyl iodide (78 mg, 0.5 mmol). When the reaction was complete, the reaction mixture was poured into buffer and the organic phase was separated. The organic phase was washed well with water, dried ( _MgSO4 ) and the solvent was evaporated in vacuo. Purification by silica gel chromatography afforded the title compound.

Example 2

17β-(N-tert-butylcarboxamide)-A-nor-androst-5-ene-3α

-Carboxylic acids and their isopropyl esters

Step a: 17β-(N-tert-butylcarboxamide)-andro-4,5-epoxy-

3-keto

3-Oxo-4-androstene-17β-carboxylic acid (11.2g, 35.4mmol) and dichloromethane (100ml) were mixed, placed under nitrogen atmosphere and cooled to 0°C with an ice bath. Triethylamine (4.1 g, 40.6 mmol) was added followed by dropwise addition of oxalyl chloride (3.8 ml, 4.4 mmol). Warm to 25°C and stir for 30 minutes. The reaction mixture was cooled to 0 °C and additional oxalyl chloride (2.91 g, 22.9 mmol) was added dropwise. Warm to 25°C and stir for 1 hour. Cool to 0°C and add tert-butylamine (17.8ml, 169mmol) dropwise, keeping the temperature below 40°C. Stir at 25°C for 30 minutes, add ice water and separate the organic phase. The aqueous phase was extracted with ethyl acetate (2X), and the combined organic phases were washed with 10% hydrochloric acid, 10% potassium hydroxide, water, then saturated sodium chloride. Drying and evaporation of the solvent in vacuo yielded 13.4 g of a yellow solid. Purification by silica gel chromatography (6:4 ethyl acetate/hexane increasing polarity to 4:6 ethyl acetate/hexane) afforded 7.9 g (60%) of 17β-(N-tert-butylcarboxamide)- Androst-4-en-3-one; mp 226-227°C. NMR-ppmδ(CDCl ₃ ) 300MHz: 5.72(s, 1H); 5.07(bs, 1H); 1.34(s, 9H); 1.17(s, 3H); 0.82(s, 3H).

17β-(N-tert-butylcarboxamide)-androst-4-en-3-one (8.5 g, 23 mmol) was dissolved in tetrahydrofuran (100 ml) and methanol (100 ml). Cool to 0°C and treat with 30% hydrogen peroxide (34ml) and 10% sodium hydroxide (10ml). Stir at 0°C for 4 hours, store at -4°C for 12 hours, then stir at 0-5°C for 4 hours. Pour into dichloromethane and water and separate the organic phase. The aqueous phase was extracted with dichloromethane, and the organic phases were combined and washed with water. Drying ( _MgSO4 ) and evaporation of the solvent in vacuo gave 8.7 g of the crude title epoxide.

Step b: 17β-(N-tert-butylcarboxamide)-androst-4-ene-4-carba

Oxy-3-one

Sodium hydroxide (8g) was dissolved in hot methanol (120ml) and heated to reflux under a nitrogen atmosphere. A solution of crude 17β-(N-tert-butylcarboxamide)-androst-4,5-epoxy-3-one (8.7 g) in methanol (20 ml) was added with stirring. Reflux for 10 minutes, pour into water and extract into dichloromethane. The organic phase is separated and dried. Evaporation of the solvent in vacuo and purification by silica gel chromatography gave 2.0 g of the title compound as a solid; mp 190-193°C. NMR-ppm δ(CDCl ₃ ) 300MHz: 5.10(bs, 1H); 3.61(s, 3H); 3.08(dt, 1H, _Jd = 12Hz, _Jt = 2Hz); 1.37(s, 9H); 1.21(s , 3H); 0.84(s, 3H).

Step c: 17β-(N-tert-butylcarboxamide)-androst-4-ene-4-methanol

Oxy-3-ol

17β-(N-tert-butylcarboxamide)-androst-4-ene-4-methoxy-3-one (2.0 g) was dissolved in absolute ethanol (20 ml). Treat with sodium borohydride (200 mg) at 25°C for 2 hours. Add water and pour into dichloromethane. The organic phase was separated and washed with water, dried ( _MgSO4 ) and the solvent evaporated in vacuo to give 2.1 g of the title compound as a foam.

Step d: 17β-(N-tert-butylcarboxamide)-androst-5-en-4-one

17β-(N-tert-butylcarboxamide)-androst-4-ene-4-methoxy-3-ol (2.1 g) was dissolved in freshly distilled acetone (8 ml) and dry dichloromethane (25 ml). Add 70% perchloric acid (2 drops) and stir at 25°C. After 15 minutes, the solution was poured into saturated sodium bicarbonate and extracted into dichloromethane. The organic phase was separated and dried ( _MgSO4 ). Purification by silica gel chromatography (30% - 50% ethyl acetate/hexanes) afforded 460 mg of the title compound as a foam. NMR-ppm δ(CDCl ₃ ) 300 MHz: 6.43 (dd, 1H, J ₁ =5 Hz, J ₂ =3 Hz); 5.12 (bs, 1H); 1.36 (s, 9H); 0.96 (s, 3H); 0.82 (s , 3H).

Step e: 17β-(N-tert-butylcarboxamide)-A-nor-andro-5-

  Isopropyl ene-3α-carboxylate

Potassium hydroxide (110 mg) was dissolved in isopropanol (3 ml), placed under a nitrogen atmosphere and cooled to 0°C. 17β-(N-tert-butylcarboxamide)-androst-5-en-4-one (112 mg, 0.30 mmol) was added, followed by iodobenzene diacetate (200 mg, 0.60 mmol). The solution was stirred at 0-5°C for 2 hours and poured into ethyl acetate. The organic phase was separated, washed with water and dried ( _MgSO4 ). Evaporation of the solvent in vacuo and purification by silica gel chromatography gave 50 mg of the title compound and its 3β-isomer which could be separated by chromatography. NMR-ppmδ(CDCl ₃ ) 300MHz: 5.55(m, 1H); 5.02(h, 1H, J=7Hz); 3.30(dd, 1H, J ₁ =7Hz, J ₂ =6Hz); 1.37(s, 9H) 1.25(d, 6H, J=7Hz); 0.95(s, 3H); 0.82(s, 3H). Step f: 17β-(N-tert-butylcarboxamide)-A-nor-andro-5-

ene-3α-carboxylic acid

Dissolve 17β-(N-tert-butylcarboxamide)-A-nor-androst-5-ene-3α-carboxylate isopropyl ester (100mg, 0.2mmol) in dichloromethane (3ml) and wash with trimethylform Silyl iodide (78 mg, 0.5 mmol) was treated. When the reaction was complete, the reaction mixture was poured into buffer and the organic phase was separated. The organic phase was washed well with water, dried ( _MgSO4 ) and the solvent was evaporated in vacuo. Purification by silica gel chromatography afforded the title compound.

Another general synthetic procedure for the preparation of steroid derivatives of formula (A) wherein R ₁ is hydrogen and of steroid derivatives of formula (D) wherein R ₁ is hydrogen is shown in Scheme B. In Scheme B, all substituents are as previously defined.

Option B

In ^general _{, the} formula ( Steroid derivatives of A) and steroid derivatives of formula (D) wherein R ₁ is hydrogen. A preferred base for this hydrolysis is, for example, lithium hydroxide, which helps to maintain the steric orientation of the [alpha]-carboxylic acid in the 3-position. The steroid derivative of formula (A) wherein _R is hydrogen and the steroid derivative of formula (D) wherein _R is hydrogen can then be separated using techniques and methods well known in the art, such as high performance liquid chromatography (HPLC). things.

The following examples describe typical syntheses as shown in Scheme B. These examples are illustrative only and are not intended to limit the scope of the invention in any way.

Example 3

17β-(N,N-diisopropylcarboxamide)-A-nor-androst-5-ene

-3α-carboxylic acid and 17β-(N,N-diisopropylcarboxamide)-A-to

Methyl-androst-3-ene-3α-carboxylic acid

Dissolve 17β-(N,N-diisopropylcarboxamide)-A-nor-androst-5-ene-3α-carboxylate methyl ester (100mg, 0.233mmol) in ethanol (4ml) and wash with lithium hydroxide ( 42mg, 10mmol) and water (1ml). Stir under nitrogen until hydrolysis is complete, evaporate the solvent, acidify with dilute hydrochloric acid and extract into ethyl acetate. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (2X) and the combined organic phases were washed with water, then saturated sodium chloride. Drying ( _MgSO4 ), solvent evaporation in vacuo and separation by HPLC gave the title compound.

Example 4

17β-(N-tert-butylcarboxamide)-A-nor-androst-5-ene-3α

-Carboxylic acid and 17β-(N-tert-butylcarboxamide)-A-nor-andro-3-

Alkene-3-carboxylic acid

17β-(N-tert-butylcarboxamide)-A-nor-androst-5-ene-3α-carboxylate isopropyl ester (100mg, 0.233mmol) was dissolved in ethanol (4ml), and lithium hydroxide (42mg , 10mmol) and water (1ml). Stir under nitrogen until hydrolysis is complete, evaporate the solvent, acidify with dilute hydrochloric acid and extract with ethyl acetate. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (2X), and the combined organic phases were washed with water, then saturated sodium chloride. The title compound was obtained after drying ( _MgSO4 ), evaporation of the solvent under reduced pressure and separation by HPLC.

Using steps similar to those of Examples 1-4, the following compounds can be prepared:

20α-(Hydroxymethyl)-A-nor-pregna-5-ene-3α-carboxylic acid;

20α-(Hydroxymethyl)-A-nor-pregna-5,11-diene-3α

-carboxylic acid;

A-nor-pregn-5-en-20-one-3α-carboxylic acid;

A-nor-pregna-5,11-dien-20-one-3α-carboxylic acid;

17β-(N-tert-butylcarboxamide)-A-nor-androst-5-ene-3α

-carboxylic acid;

17β-(N-tert-butylcarboxamide)-A-nor-andro-5,11-di

En-3α-carboxylic acid;

17β-(N,N-diisopropylcarboxamide)-A-nor-andro-5,11

- diene-3α-carboxylic acid;

20α-(Hydroxymethyl)-A-nor-pregna-3-ene-3-carboxylic acid;

20α-(Hydroxymethyl)-A-norpregna-3,11-diene-3-carboxy

acid;

A-nor-pregn-3-en-20-one-3-carboxylic acid;

A-nor-pregna-3,11-dien-20-one-3-carboxylic acid;

17β-(N,N-diisopropylcarboxamide)-A-nor-andro-3,11

- Diene-3-carboxylic acid;

17β-(N-tert-butylcarboxamide)-A-nor-androst-3-ene-3-

carboxylic acid;

17β-(N-tert-butylcarboxamide)-A-nor-3,11-diene

-3-Carboxylic acid.

Scheme C shows a general synthetic procedure for the preparation of compounds of formula (B). In Scheme C, all substituents are as previously defined. In addition, the term "φSe" refers to a phenylselenyl group; "Z" refers to a metal counter ion or a trimethylsilyl group; and "X" refers to a halo group.

Plan C

In general, steroid derivatives of formula (B) can be prepared from steroid derivatives of formula (A ₁ ) in a three-step process.

In Scheme C, step a, the appropriate A-nor- ^Δ5 -steroid-3-carboxylate derivative ( _A1 ) is treated with a metal base such as an alkaline earth metal base, Scheme A, step e, to afford the corresponding enol ester (6). The enol ester (6) can be converted to the corresponding silylketene acetal (6') by treatment with trimethylsilyl chloride according to known procedures and techniques.

In step b, the enol ester (6) or silylketene acetal (6') is converted to the corresponding A-nor- Δ ⁵ -steroid-3-diphenylselenium derivatives (7), among which phenylselenyl bromide is preferably used.

In step c, the corresponding A-nor-Δ ⁵ -steroid-3-diphenylselenium derivative (7) is converted to its selenium oxide, followed by Hydrolysis by formic acid treatment affords the corresponding A-nor-Δ ² ,Δ ⁵ -steroid-3-carboxylate derivative (B ₁ ). A preferred oxidizing agent is hydrogen peroxide.

The compound of formula (B ₁ ) can be converted into its corresponding free acid by hydrolysis according to Scheme A, step f and Scheme B.

The following example is a typical synthetic method of Scheme C, which is only used for illustration, but not to limit the scope of the present invention.

Example 5

17β-(N,N-diisopropylcarboxamide)-A-nor-andro-2,5

-Diene-3-carboxylic acid methyl ester

Step a: 17β-(N,N-diisopropylcarboxamide)-A-nor-androgen

-5-ene-3-[lithium (enol methyl ester)]

Under argon at -70°C, 17β-(N,N-diisopropylcarboxamide)-A-nor-androst-5-ene-3α-carboxylic acid methyl ester (430mg, 1.0mmol, obtained from the corresponding To a stirred solution of lithium diisopropanamide (1.1 mmol) in THF (11 mL) in anhydrous THF (25 mL) was added over 15 minutes. Stirring at -70°C gave the title compound.

Step b: Methyl 17β-(N,N-diisopropylcarboxamide)-A-nor-androst-5-ene-3-diphenylselenium-3-carboxylate

After stirring the 17β-(N,N-diisopropylcarboxamide)-A-nor-androst-5-ene-3-lithium [(enol methyl ester)] reaction mixture at -70°C for 15 minutes, add A solution of phenylselenyl bromide (260mg, 1.1mmol) in THF (5ml). The mixture was warmed to 25°C over 1 hour, then poured into 1N HCl solution. Extracted with dichloromethane, the organic phase was dried over anhydrous _MgSO4 . Concentration under reduced pressure, flash chromatography on a silica gel column (eluted with 10% ethyl acetate/hexane) gave the title compound.

Another way of step b: 17β-(N,N-diisopropylcarboxamide)-A-

Nor-androst-5-ene-3-diphenylselenium-3-carboxylate methyl ester

After stirring 17β-(N,N-diisopropylcarboxamide)-A-nor-androst-5-ene-3-lithium [(enol methyl ester)] at -70°C for 15 minutes, chlorine was added by syringe trimethylsilane (140 μl, 1.1 mmol). The reaction mixture was allowed to warm to 25°C over 30 minutes, then concentrated under reduced pressure. The residue was taken up in anhydrous dichloromethane (25ml), cooled to 0°C, and the mixture was treated with a solution of phenylselenyl bromide (260mg, 1.1mmol) in THF (5ml). The mixture was allowed to warm to 25°C over 1 hour, then it was poured into 1N HCl solution. Extract with dichloromethane and dry the organic phase with anhydrous _MgSO4 . After concentration under reduced pressure, flash chromatography on a silica gel column (eluted with 10% ethyl acetate/hexane) gave the title compound.

Step c: 17β-(N,N-diisopropylcarboxamide)-A-nor-androgen

-Methyl 2,5-diene-3-carboxylate

17β-(N,N-diisopropylcarboxamide)-A-nor-androst-5-ene-3-diphenylselenium-3-carboxylic acid methyl ester was dissolved in anhydrous THF (20ml), and washed with a small Batches of hydrogen peroxide were treated until no selenide was present by TLC analysis. With stirring, the solution was warmed up to the point that no selenium oxide was present by TLC analysis. The title compound was obtained after concentration under reduced pressure and flash chromatography on a silica gel column (eluted with 10% ethyl acetate/hexane).

Example 6

17β-(N,N-diisopropylcarboxamide)-A-nor-andro-2,5

-diene-3-carboxylic acid

Method 1: Methyl 17β-(N,N-diisopropylcarboxamide)-A-nor-andro-2,5-diene-3-carboxylate (100 mg, 0.233 mmol) was dissolved in dichloromethane (3ml) and treated with trimethylsilyl iodide (78mg, 0.5mmol). After the reaction was complete, the reaction mixture was poured into buffer, and the organic phase was separated. The organic phase was washed well with water, dried over anhydrous MgSO ₄ , and the solvent was evaporated under reduced pressure. Purify by silica gel chromatography to give the title compound.

Method 2: Dissolve methyl 17β-(N,N-diisopropylcarboxamide)-A-nor-andro-2,5-diene-3-carboxylate (100mg, 0.233mmoL) in ethanol (4ml ), and treated with lithium hydroxide (42 mg, 10 mmol) and water. Stir under nitrogen until hydrolysis is complete, evaporate the solvent, acidify with dilute hydrochloric acid and extract with ethyl acetate. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (2X), the combined organic phases were washed with water and saturated NaCl, dried ( _MgSO4 ), the solvent was evaporated under reduced pressure and purified by silica gel chromatography to give the title compound.

Example 7

17β-(N-tert-butylcarboxamide)-A-nor-andro-2,5-diene

-3-Carboxylate isopropyl ester

Step a: 17β-(N-tert-butylcarboxamide)-A-nor-andro-5-

En-3-[lithium (isopropylenol)]

17β-(N-tert-butylcarboxamide)-A-nor-androst-5-ene-3α-carboxylate isopropyl ester (430 mg, 1.0 mmol, Example 2, step e) To a stirred solution of anhydrous THF was added a solution of lithium diisopropanamide (1.1 mmol) in THF (11 ml) over 15 minutes. Stirring at -70°C gave the title compound.

Step b: 17β-(N-tert-butylcarboxamide)-A-nor-andro-5-

Isopropyl ene-3-diphenylselenium-3-carboxylate

After stirring 17β-(N-tert-butylcarboxamide)-A-nor-androst-5-ene-3-[lithium(isopropylenol)] at -70°C for 15 minutes, add phenylselenyl bromide in one portion (260mg, 1.1mmol) in THF (5ml). The mixture was allowed to warm to 25°C over 1 hour, then it was poured into 1N HCl solution. Extracted with dichloromethane, the organic phase was dried over anhydrous _MgSO4 . After concentration under reduced pressure, flash chromatography on a silica gel column (eluted with 10% ethyl acetate/hexane) gave the title compound.

Alternative route to step b: 17β-(N-tert-butylcarboxamide)-A-nor

-Androst-5-ene-3-diphenylselenium-3-carboxylate isopropyl ester

After stirring 17β-(N-tert-butylcarboxamide)-A-nor-androst-5-ene-3-[lithium(enolisopropyl ester)] at -70°C for 15 minutes, trichloride was added by syringe Methylsilane (140 μl, 1.1 mmol). The mixture was allowed to warm to 25°C over 30 minutes, then concentrated under reduced pressure. The residue was taken up in anhydrous dichloromethane (25ml), cooled to 0°C and treated with a solution of phenylselenyl bromide (260mg, 1.1mmol) in THF (5ml). The mixture was allowed to warm to 25°C over 1 hour, then it was poured into 1N HCl solution. Extracted with dichloromethane, the organic phase was dried over anhydrous _MgSO4 . After concentration under reduced pressure, flash chromatography on a silica gel column (eluted with 10% ethyl acetate/hexane) gave the title compound.

Step c: 17β-(N-tert-butylcarboxamide)-A-nor-andro-2,

Isopropyl 5-diene-3-carboxylate

Dissolve isopropyl 17β-(N-tert-butylcarboxamide)-A-nor-androst-5-ene-3-diphenylselenium-3-carboxylate in anhydrous THF (20 ml), and Hydrogen oxide treatment until TLC analysis no residual selenide. The solution was allowed to warm with stirring until TLC analysis was free of selenium oxide. After concentration under reduced pressure, flash chromatography on a silica gel column (eluted with 10% ethyl acetate/hexane) gave the title compound.

Example 8

17β-(N-tert-butylcarboxamide)-A-nor-andro-2,5-diene

-3-carboxylic acid

Method 1: Dissolve 17β-(N-tert-butylcarboxamide)-A-nor-andro-2,5-diene-3-carboxylate isopropyl ester (100mg, 0.233mmol) in dichloromethane (3ml ), treated with trimethylsilyl iodide (78 mg, 0.5 mmol). After the reaction was complete, the reaction mixture was poured into buffer, and the organic phase was separated. The organic phase was washed well with water, dried ( _MgSO4 ), and the solvent was evaporated under reduced pressure. The title compound is obtained after chromatography on silica gel.

Method 2: Dissolve 17β-(N-tert-butylcarboxamide)-A-nor-andro-2,5-diene-3-carboxylic acid isopropyl ester (100mg, 0.2mmol) in ethanol (4ml), and treated with lithium hydroxide (42mg, 10mmol) and water (1ml). Stir under a nitrogen atmosphere until the hydrolysis is complete, evaporate the solvent, acidify with dilute hydrochloric acid, and extract with ethyl acetate. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (2X), and the combined organic phases were washed with water and then with saturated sodium chloride. Dry ( _MgSO4 ), evaporate the solvent under reduced pressure and chromatograph on silica gel to give the title compound.

The following compounds can be prepared in the same steps as in Examples 5-8:

20α-(Hydroxymethyl)-A-nor-pregna-2.5-diene-3α-carboxylic acid;

20α-(Hydroxymethyl)-A-nor-pregna-2.5,11-triene-3-carboxylic acid;

A-norpregna-2,5-dien-20-one-3-carboxylic acid;

A-nor-pregna-2,5,11-triene-20-one-3-carboxylic acid;

17β-(N-tert-butylcarboxamide)-A-nor-andro-2,5,11-triene-3-carboxylic acid;

17β-(N,N-diisopropylcarboxamide)-A-nor-androst-2,511-triene-3-carboxylic acid.

Scheme D shows the general synthetic procedure for the preparation of steroid derivatives of formula (C) wherein all substituents are as previously defined.

Plan D

In general, steroid derivatives of formula (C) can be prepared from steroid derivatives of formula (A ₁ ) in a two-step process.

In step a, the alkene functionality of an appropriate A-nor- ^Δ5 -steroid-3-carboxylate derivative of formula ( _A1 ) can be converted into the corresponding dibromosteroid derivative of formula (8). For example, A-nor- ^Δ5 -steroid-3-carboxylate derivatives of formula ( _A1 ) can be reacted with pyridinium bromide perbromide in a suitable aprotic solvent such as dichloromethane.

In step b, the dibromo steroid derivative of formula (8) is converted into the corresponding diene steroid derivative of formula (C ₁ ). For example, a suitable dibromosteroid derivative of formula (8) can be dehydrogenated with a suitable non-nucleophilic base such as 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) Halogenated.

Compounds of formula (C ₁ ) can be converted to their corresponding free acids by hydrolysis as described in Scheme A, step f or Scheme B.

The following examples illustrate typical synthetic methods shown in Scheme D and are used here for illustration only, but not to limit the scope of the invention.

Example 9

17β-(N,N-Diisopropylcarboxamide)-A-nor-andro-3,6-diene-3-carboxylic acid methyl ester

Step a and step b: Dissolve 17β-(N,N-diisopropylcarboxamide)-A-nor-androst-5-ene-3α-carboxylate methyl ester (50 mg, 0.11 mmol) in dichloromethane (2ml), treated with pyridinium bromide bromide (35mg, 0.11mmol). After stirring at room temperature for 1.2 hours, DBU (0.5 ml) was added and heated at 50°C for 2 hours. After cooling it was poured into a mixture of dilute hydrochloric acid and dichloromethane. The organic phase was separated, dried ( _MgSO4 ) and the solvent was evaporated under reduced pressure to give 35 mg of the title compound.

Example 10

17β-(N,N-diisopropylcarboxamide)-A-nor-andro-3,6-diene-3-carboxylic acid

Method 1: Methyl 17β-(N,N-diisopropylcarboxamide)-A-nor-andro-3,6-diene-3-carboxylate (100 mg, 0.233 mmol) was dissolved in dichloromethane (3ml), treated with trimethylsilyl iodide (78mg, 0.5mmol). After the reaction was complete, the reaction mixture was poured into buffer, and the organic phase was separated. The organic phase was washed well with water, dried ( _MgSO4 ) and the solvent was evaporated under reduced pressure to give the title compound after purification by silica gel chromatography.

Method 2: Dissolve methyl 17β-(N,N-diisopropylcarboxylate)-A-nor-andro-3,6-diene-3-carboxylate (35 mg) in methanol (5 ml), Treat with 1N lithium hydroxide (0.5ml) and solid lithium hydroxide (50mg). Stir under nitrogen for 12 hours, dilute with water, filter through celite and acidify with acetic acid (0.5ml). After filtration, the mother liquor was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and then with saturated sodium chloride. Drying (MgSO ₄ ), evaporation of the solvent under reduced pressure and purification by silica gel column chromatography gave the title compound. NMR-ppmδ(CDCl ₃ ) 300MHz: 7.06(dd, 1H, J ₁ =10Hz, J ₂ =3Hz); 6.07(bd, _Jd =10Hz); 4.21(h, 1H, J=7Hz); 3.41(h , 1H, J=7Hz); 1.43(d, 3H, J=7Hz); 1.39(d, 3H, J=7Hz); 1.23(d, 3H, J=7Hz); 1.16(d, 3H, J=7Hz ); 0.97(s, 3H); 0.86(s, 3H).

Example 11

Isopropyl 17β-(N-tert-butylcarboxamide)-A-nor-andro-3,6-diene-3-carboxylate

Steps a and b: Isopropyl 17β-(N-tert-butylcarboxamide)-A-nor-andro-3,6-diene-3-carboxylate (50 mg, 0.11 mmol) was dissolved in dichloromethane (2ml), treated with pyridinium bromide bromide (35mg, 0, 11mmol) and stirred at room temperature for 2 hours. DBU (2ml) was added to the solution, the solvent was evaporated under reduced pressure, heated at 50°C for 2 hours, the reaction mixture was poured into dilute hydrochloric acid, and extracted with dichloromethane. The organic phase was separated, dried ( _MgSO4 ) and the solvent was evaporated under reduced pressure. After purification by silica gel chromatography, 35 mg of the title compound were obtained. NMR-ppm δ(CDCl ₃ ) 300 MHz: 7.03 (dd, 1H, J ₁ =10 Hz, J ₂ =3 Hz); 5.99 (bd, 1H, J _d =10 Hz); 5.11 (bs, 1H); 5.08 (h, 1H , J=7Hz); 1.36(s, 9H); 1.28(d, 3H, J=7Hz); 1.26(d, 3H, J=7Hz); 0.94(s, 3H); 0.86(s, 3H).

Example 12

17β-(N-tert-butylcarboxamide)-A-nor-andro-3,6-diene

-3-carboxylic acid

Method 1: Dissolve 17β-(N-tert-butylcarboxamide)-A-nor-andro-3,6-diene-3-carboxylate isopropyl ester (100mg, 0.2mmol) in dichloromethane (3ml ), treated with trimethylsilyl iodide (78 mg, 0.5 mmol). After the reaction was complete, the reaction mixture was poured into buffer, and the organic phase was separated. The organic phase was washed well with water, dried ( _MgSO4 ) and the solvent was evaporated under reduced pressure to give the title compound after purification by silica gel chromatography.

Method 2: Dissolve 17β-(N-tert-butylcarboxamide)-A-nor-andro-3,6-diene-3α-carboxylate isopropyl ester (35mg) in methanol (5ml) and wash with 1N hydrogen Lithium oxide (0.5ml) and solid lithium hydroxide (30mg) were treated. Refluxed for 4 hours under a nitrogen atmosphere, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was separated, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and then with saturated sodium chloride. The title compound was obtained after drying ( _MgSO4 ), evaporation of the solvent under reduced pressure and purification by silica gel chromatography (25% ethyl acetate/hexanes). NMR-ppm δ(CDCl ₃ ) 300 MHz: 7.06 (dd, 1H, J ₁ =10 Hz, J ₂ =3 Hz); 6.05 (bd, 1H, J _d =10 Hz); 5.11 (bs, 1H); 1.37 (s, 9H ); 0.95(s, 3H); 0.86(s, 3H).

By the steps similar to Examples 9-12, the following compounds can be prepared:

20α-(Hydroxymethyl)-A-nor-pregna-3,6-diene-3-carboxy

acid;

20α-(Hydroxymethyl)-A-nor-pregna-3,6,11-triene-

3-carboxylic acid;

A-nor-pregna-3,6-dien-20-one-3-carboxylic acid;

A-nor-pregna-3,6,11-triene-20-one-3-carboxylic acid;

17β-(N-tert-butylcarboxamide)-A-nor-andro-3,6,11

- Triene-3-carboxylic acid;

17β-(N,N-diisopropylcarboxamide)-A-nor-andro-3,6

11-triene-3-carboxylic acid.

Another aspect of the present invention is to provide a method for treating a patient suffering from a DHT-mediated disease or symptom, comprising making the patient take an effective 5-alpha-reductase inhibitory amount of formula (A), (B), (C ), (D) compounds.

A "patient" as used herein refers to a warm-blooded animal, such as a human, suffering from a DHT-mediated disease or condition. A DHT-mediated disease or condition is a disease or condition associated with increased androgen activity due to excessive formation of DHT. DHT-mediated diseases or conditions include acne, benign prostatic hyperplasia, androgenic alopecia (common baldness caused by androgen in genetically susceptible men and women), seborrhea, and female hirsutism.

Inhibition of steroid 5-α-reductase in patients with DHT-mediated diseases or symptoms can reduce or control the disease or symptoms by reducing the level of DHT in infected tissues. The "alleviation or control of disease or symptoms" mentioned herein refers to the slowing down, interruption, retardation or suspension of disease symptoms, not necessarily the complete elimination of the disease. Infected tissue is tissue in which DHT levels are so high that DHT-mediated disease or symptoms result.

For example, DHT levels in the skin tissue of people with acne are elevated. Symptoms of acne include skin rashes and skin lesions. Inhibiting the skin's 5-alpha-reductase will lower DHT levels and control acne symptoms. DHT levels in the prostate are elevated in men with benign prostatic hypertrophy. Symptoms of benign prostatic hypertrophy include an enlarged prostate. Inhibition of prostate 5-alpha-reductase will reduce DHT levels and control prostate growth.

Obviously, patients with DHT-mediated diseases or conditions can be treated as well as prevented. Those skilled in the art of medical diagnosis and treatment have no difficulty in identifying patients with DHT-mediated diseases or conditions.

The effective 5-alpha-reductase inhibitory amount of formula (A), (B), (C), (D) compound refers to patient when single dose or multi-dose administration, the amount of compound can effectively inhibit 5-alpha-reductase The enzyme or lowers DHT in tissues exhibiting DHT-mediated diseases or symptoms. For example, in the treatment of acne, the effective 5-α-reductase inhibitory amount of compound (A), (B), (C) or (D) means that it can effectively inhibit the activity of 5-α-reductase in the skin or reduce the amount of 5-α-reductase in the skin. Compound amount for DHT levels. In the treatment of prostatic hypertrophy, the effective 5-alpha-reductase inhibitory amount of compound (A), (B), (C) or (D) means that it can effectively inhibit the activity of 5-alpha-reductase in the prostate or reduce DHT in the prostate levels of compounds.

A therapeutically effective amount of a compound of formula (A), (B), (C) or (D) is expected to be from about 0.1 to 400 mg/kg body weight/day. A preferred range is about 0.1-200 mg/kg body weight/day.

In the treatment of patients infected with the above diseases, the compound of formula (A), (B), (C) or (D) can be administered in any dosage form or manner that can provide a biologically effective amount, including oral and parenteral administration . For example, the administration of the compound of formula (A), (B), (C) or (D) can be oral administration, subcutaneous injection, intramuscular injection, intravenous injection, cortical administration, intranasal administration, rectal administration, etc. . Oral or transdermal administration is usually preferred. Those skilled in the art of formulation can easily select the appropriate dosage form and mode of administration according to the specific properties of the selected compound, the symptoms of the disease to be treated, the stage of the disease and other relevant factors.

The compounds can be used alone or in combination with pharmaceutically acceptable carriers or excipients in the form of pharmaceutical compositions, the amount and nature of which will depend on the solubility and chemical properties of the selected compound, the route of administration and conventional pharmaceutical practice. . The compounds of the present invention, while effective in themselves, may also be formulated and used in the form of their pharmaceutically acceptable salts for stabilization, crystallization, increased solubility, and the like.

Another aspect of the invention provides compositions comprising a compound of formula (A), (B), (C) or (D) in admixture or association with one or more inert carriers. These compositions are useful, for example, as assay standards, as a convenient form for bulk shipment in large quantities, and as pharmaceutical compositions. Detectable amounts of compounds of formula (A), (B), (C) or (D) are those amounts that are readily detectable by known detection procedures and techniques commonly used by those skilled in the art. Detectable amounts of compounds of formula (A), (B), (C) or (D) will generally range from about 0.001 to 75% by weight of the composition. An inert carrier can be any material which does not degrade or covalently react with the compound of formula (A), (B), (C) or (D). Examples of suitable inert carriers are water; aqueous buffers such as those commonly used in high performance liquid chromatography (HPLC) analysis; organic solvents such as acetonitrile, ethyl acetate, hexane, etc.; and pharmaceutically acceptable carriers or excipients .

More specifically, the present invention provides pharmaceutical combinations comprising a therapeutically effective amount of a compound of formula (A), (B), (C) or (D) in admixture or association with one or more pharmaceutically acceptable carriers or excipients things.

Pharmaceutical compositions are prepared by methods well known in the art of pharmacy. The carrier or excipient can be a solid, semi-solid or liquid material which acts as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition can be made into a form suitable for oral or parenteral use, and can be applied to patients in the form of tablets, capsules, topical creams or gels, suppositories, solutions or suspensions, and the like.

The compounds of the present invention can be administered orally, eg, with an inert diluent or edible carrier. It can be enclosed in capsules or compressed into tablets. The compound can be blended with excipients to make tablets, tablets, capsules, glycerin oil, suspension, syrup, candy or chewing gum, etc. for oral administration. These preparations should contain at least 4% of the compound of the present invention as active ingredient, but depending on the particular dosage form, the active ingredient may range from 4 to 70% by weight per unit. The amount of compound in the composition should be such as to obtain a suitable dosage. Preferred compositions and formulations of the invention are prepared so that an oral dosage unit contains from 0.1 to 300 mg of the compound of the invention.

Tablets, pills, capsules and lozenges, etc. may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose; disintegrants such as Alginic acid, Primogel, corn starch, etc.; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweeteners such as sucrose or saccharin or flavoring agents such as peppermint, methyl salicylate, or orange odorant. When the unit dosage form is a capsule, it may contain, in addition to the above materials, a liquid carrier such as polyethylene glycol or a fatty oil. Other unit dosage forms can contain various materials which modify the physical form of the preparation, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac or other enteric coating agents. A syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in the preparation of the various compositions described above should be pharmaceutically pure and nontoxic in the amounts employed.

For parenteral administration, the compounds of the invention may be incorporated into solutions or suspensions. These preparations should contain at least 0.1% of the compound of the invention, but it may be present in an amount ranging from 0.1 to 50% by weight of the composition. The amount of the compound of the invention in said composition is such that a suitable dosage will be obtained. Preferred compositions and formulations of the invention are prepared such that dosage units for parenteral administration contain 0.5-100 mg of a compound of the invention.

The solution or suspension may also contain one or more of the following adjuvants: sterile diluents such as water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or hydroxy Methyl benzoate; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or sulfates, and strength-adjusting agents such as sodium chloride or dextrose . The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

As with any class of compounds that are structurally related with certain generalities, certain classes and configurations of compounds of formula (A), (B), (C) or (D) are preferred for their end use.

Preferred compounds of the invention are those wherein _R1 is hydrogen. Compounds of the invention in which _R2 is 1-(hydroxymethyl)ethyl, N,N-diisopropylcarboxamide, N-tert-butylcarboxamide and 1-oxyethyl are also preferred.

Claims (1)

1. A process for preparing a compound of formula (D ₂ ),

in Dashed lines indicate dispensable double bonds; R ₂ is C ₁ -C ₆ alkanol; C ₁ -C ₆ alkanone; CON(R ₃ )(R ₄ ), wherein R ₃ and R ₄ are each independently hydrogen or C ₁ -C ₆ alkyl , or -(CH ₂ )x-Ar-(M)y, where x is 0, 1 or 2, Ar is phenyl, y is 0, 1 or 2, M is C ₁ -C ₆ alkoxy, halogen , C ₁ -C ₆ alkyl, or -S(O)zR ₅ , wherein R ₅ is C ₁ -C ₆ alkyl, z is 0, 1 or 2, the method comprises the following steps: (a) reacting a compound of formula (A ₁ ) with lithium hydroxide and isolating the desired product.